Metabolic clearance of cholesterol

By Umesh D. Wankhade

Cholesterol is a critical player in many biological processes. At an optimal concentration in the cell, it performs essential roles such as maintaining cell-membrane structure and acts as a precursor to several necessary metabolites, including steroid hormones and bile acids. An unperturbed cholesterol efflux process is necessary to maintain the right amount of intracellular cholesterol, because most cells cannot break it down. Conversely, deficient cholesterol efflux, leading to cholesterol overloading in cells, can cause fat-laden immune cells and the development of atherosclerotic plaques that can lead to heart attacks and cardiac strokes.

In a recent minireview published in the Journal of Biological Chemistry, Michael Phillips at the Perelman School of Medicine at the University of Pennsylvania discussed the molecular mechanisms of cellular cholesterol efflux. He explained the basic mechanism of cholesterol turnover in the body and covered the latest developments in the field.

Appropriate carriers and acceptors of cholesterol, such as high-density lipoprotein in the extracellular medium, clear cholesterol through the liver and prevent overloading of the molecule in the blood system. Cholesterol transport is initiated through efflux of free cholesterol from the plasma membrane to HDL. Cholesterol efflux in a cell via HDL is performed through passive and active pathways.

Summary of the molecular mechanism by which ABCA1 activity in the plasma membrane of cells promotes efflux of PL and cholesterol to extracellular apoA-I and formation of nascent HDL particles.

The passive process includes simple diffusion via aqueous phase and facilitated diffusion, which is mediated by a protein called the scavenger receptor class B, type 1. The active pathways are mediated by the ATP binding cassette, or ABC, transporters ABCA1 and ABCG1. The necessity of these transporter proteins in cholesterol efflux is well known, because the combined deficiency of these transporters leads to an accumulation of cholesterol in macrophages and accelerates atherosclerosis in mice.

As explained in the review, our bodies need cholesterol for basic metabolic functions. An in-depth understanding of the cholesterol efflux transport process will help researchers formulate better therapeutic alternatives that will increase HDL cholesterol and speed up the efflux process to tackle the problem of cholesterol disorders, such as dyslipidemia, in which there is an abnormal amount of cholesterol in the bloodstream.

Umesh D. Wankhade (udvets@gmail.com) is a postdoctoral fellow at the National Institute of Health’s diabetes, endocrinology and obesity branch.